From Karolinska Institutet and Stockholm County Council, Stockholm, Sweden; Örebro University Hospital, Örebro, Sweden; University of Nottingham, Nottingham, United Kingdom; Columbia University College of Physicians and Surgeons, New York, New York; and Medical Products Agency, Uppsala, Sweden.

Peter Ström, MSc

From Karolinska Institutet and Stockholm County Council, Stockholm, Sweden; Örebro University Hospital, Örebro, Sweden; University of Nottingham, Nottingham, United Kingdom; Columbia University College of Physicians and Surgeons, New York, New York; and Medical Products Agency, Uppsala, Sweden.

Cecilia Lundholm, MSc

From Karolinska Institutet and Stockholm County Council, Stockholm, Sweden; Örebro University Hospital, Örebro, Sweden; University of Nottingham, Nottingham, United Kingdom; Columbia University College of Physicians and Surgeons, New York, New York; and Medical Products Agency, Uppsala, Sweden.

Sven Cnattingius, MD, PhD

From Karolinska Institutet and Stockholm County Council, Stockholm, Sweden; Örebro University Hospital, Örebro, Sweden; University of Nottingham, Nottingham, United Kingdom; Columbia University College of Physicians and Surgeons, New York, New York; and Medical Products Agency, Uppsala, Sweden.

Anders Ekbom, MD, PhD

From Karolinska Institutet and Stockholm County Council, Stockholm, Sweden; Örebro University Hospital, Örebro, Sweden; University of Nottingham, Nottingham, United Kingdom; Columbia University College of Physicians and Surgeons, New York, New York; and Medical Products Agency, Uppsala, Sweden.

Åke Örtqvist, MD, PhD

From Karolinska Institutet and Stockholm County Council, Stockholm, Sweden; Örebro University Hospital, Örebro, Sweden; University of Nottingham, Nottingham, United Kingdom; Columbia University College of Physicians and Surgeons, New York, New York; and Medical Products Agency, Uppsala, Sweden.

Nils Feltelius, MD, PhD

From Karolinska Institutet and Stockholm County Council, Stockholm, Sweden; Örebro University Hospital, Örebro, Sweden; University of Nottingham, Nottingham, United Kingdom; Columbia University College of Physicians and Surgeons, New York, New York; and Medical Products Agency, Uppsala, Sweden.

Fredrik Granath, PhD

From Karolinska Institutet and Stockholm County Council, Stockholm, Sweden; Örebro University Hospital, Örebro, Sweden; University of Nottingham, Nottingham, United Kingdom; Columbia University College of Physicians and Surgeons, New York, New York; and Medical Products Agency, Uppsala, Sweden.

Olof Stephansson, MD, PhD

From Karolinska Institutet and Stockholm County Council, Stockholm, Sweden; Örebro University Hospital, Örebro, Sweden; University of Nottingham, Nottingham, United Kingdom; Columbia University College of Physicians and Surgeons, New York, New York; and Medical Products Agency, Uppsala, Sweden.

From Karolinska Institutet and Stockholm County Council, Stockholm, Sweden; Örebro University Hospital, Örebro, Sweden; University of Nottingham, Nottingham, United Kingdom; Columbia University College of Physicians and Surgeons, New York, New York; and Medical Products Agency, Uppsala, Sweden.

Disclaimer: This article represents the views of the authors and does not necessarily represent those of the Swedish Medical Products Agency, which employed one of the authors (N.F.) at the time of the study.

Acknowledgment: The authors thank Professor Ingemar Persson for his work with the H1N1 cohort.

Grant Support: This project was supported by grants from the Swedish Research Council (Medicine, 2010-4202) and the Swedish Council for Working Life and Social Research (FAS, 2010-4202).

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.

Reproducible Research Statement:Study protocol: This study had no formal protocol. Statistical code: Available from Dr. Ludvigsson (e-mail, jonasludvigsson@yahoo.com). Data set: Available from the Swedish National Board of Health and Welfare (www.socialstyrelsen.se/english).

Abstract

Background:

Earlier studies reporting varying risk estimates for congenital malformation in offspring of mothers undergoing vaccination against H1N1 influenza during pregnancy did not consider the potential role of confounding by familial (genetic and shared environmental) factors.

Objective:

To evaluate an association between maternal H1N1 vaccination during pregnancy and offspring malformation, with familial factors taken into account.

Design:

Population-based prospective study.

Setting:

Sweden.

Participants:

Liveborn offspring born between 1 October 2009 and 1 October 2011 to mothers receiving monovalent AS03-adjuvanted H1N1 influenza vaccine (Pandemrix [GlaxoSmithKline]) during pregnancy. A total of 40 983 offspring were prenatally exposed to the vaccine, 14 385 were exposed within the first trimester (14 weeks), and 7502 were exposed during the first 8 weeks of pregnancy. Exposed offspring were compared with 197 588 unexposed offspring. Corresponding risks in exposed versus unexposed siblings were also estimated.

Congenital malformation was observed in 2037 (4.97%) exposed offspring and 9443 (4.78%) unexposed offspring. Adjusted risk for congenital malformation was 4.98% in exposed offspring versus 4.96% in unexposed offspring (risk difference, 0.02% [95% CI, −0.26% to 0.30%]). The corresponding risk differences were 0.16% (CI, −0.23% to 0.56%) for vaccination during the first trimester and 0.10% (CI, −0.41% to 0.62%) for vaccination in the first 8 weeks. Using siblings as comparators yielded no statistically significant risk differences.

Limitations:

The study was based on live births, and the possibility that data on miscarriage or induced abortion could have influenced the findings cannot be ruled out. Study power was limited in analyses of specific malformations.

Conclusion:

When intrafamilial factors were taken into consideration, H1N1 vaccination during pregnancy did not seem to be linked to overall congenital malformation in offspring, although risk increases for specific malformations could not be ruled out completely.

Primary Funding Source:

Swedish Research Council and Swedish Council for Working Life and Social Research.